[Primary extra-axial chondroid chordoma of the anterior nasal septum: case report of a rare chordoma with literature review]. / Primäres extraaxiales chondroides Chordom des anterioren Nasenseptums: Fallbericht eines seltenen Chordoms mit Literaturübersicht.

An 87-year-old patient reported a nodular, progressively enlarging mass of the anterior nasal septum leading to partial obstruction of the nostrils. The tumor showed no infiltration of the subcutis, bone, or paranasal sinuses in imaging or intraoperatively. Histological examination revealed a chondroid tumor with lobular growth and physaliferous cell morphology. Immunohistochemistry revealed a brachyury-positive tumor without EWSR1 rearrangement, leading to the diagnosis of a chondroid chordoma. The reported case demonstrates the differential diagnostic considerations pertaining to this rare tumor, which can also have an untypical and very rare extra-axial location. Review of the literature identified 34 primary extraosseous chordomas of the nose, nasopharynx, and paranasal sinuses, and allowed the nasal chordoma presented herein to be included in this group of extra-axial chordomas.

U-CH17P, -M and -S, a new cell culture system for tumor diversity and progression in chordoma.

Chordoma is a rare bone tumor with a known intrinsic heterogeneity. Here, we address this tumor heterogeneity in a new cell culture model for tumor diversity and progression in chordoma. The three cell lines U-CH17P, U-CH17M, and U-CH17S were established from a primary sacral chordoma and its derived metastases, a soft tissue and a skin metastasis, respectively. The lesions had divergent differentiation patterns which are conserved in the derived cell lines making them a suitable in vitro model for the analysis of tumorigenesis in chordoma. A common feature of the three cell lines is the expression of typical chordoma markers, such as Brachyury, vimentin, cytokeratins, EMA and S100 protein. A comparison of the genomic aberrations by array comparative genomic hybridization of the cell lines and the corresponding parental tumor tissues revealed that the precursor cells of U-CH17P, U-CH17M and U-CH17S were already present in the primary tumor. Therefore, we show that clonal diversity of this chordoma exists in the primary tumor and that not all of these subclones tend to metastasize. All cell lines had a CDKN2A loss. A comparison of the gene expression profiles of the cell lines revealed significant differences in the expression of several genes like MAGEC2 and SEMA6A known to be associated with the tendency to metastasize or proliferation and migration. Since the underlying mechanisms of tumor progression in chordoma are still largely unclear, the three U-CH17 cell lines are a suitable in vitro model for elucidating chordoma oncobiology.

[New aspects on giant cell tumor of bone]. / Neue Aspekte zum Riesenzelltumor des Knochens.

A giant cell tumor of bone (GCTB) is one of the giant cell-rich lesions of bone and has to be differentiated from non-ossifying fibroma, aneurysmatic bone cyst, chondroblastoma, "brown tumor" and osteosarcoma containing giant cells. A hallmark of GCTB is the presence of the distinct histone 3 (H3F3A) mutation G34W and its detection either by sequencing methods or using immunohistochemistry with a novel antibody against this mutational site. Worrisome is the fact that under denosumab therapy a histological change of the lesions can be seen and there are first reports of sarcomas arising after therapy. When diagnosing giant cell-rich lesions, pathologists should be aware of the various differential diagnoses and morphological spectrum within GCTB.

[Presacral lesion at the rima ani]. / Präsakrale Raumforderung an der Rima ani.

A 26-year-old woman presented with a painful bulge at the rima ani. The tumor was located in the presacral region. Histological examination revealed a well-circumscribed biphenotypical tumor with papillary configured myxoid areas and strongly sclerosing regions. This case of a myxopapillary ependymoma is a rare example of a myxoid neoplastic lesion in the sacral region.

[Notochordal tumors : Benign notochordal tumors and chordomas]. / Notochordale Tumoren : Benigne notochordale Tumoren und Chordome.

Benign notochordal tumors (BNCT) and chordomas are primary bone tumors of the spine with a predominant localization in the sacrum and clival region followed by the vertebral bodies. Besides the most common variant (NOS [not otherwise specified] with hepatoid or renal carcinoma cell-like differentiation) chordomas with chondroid, and polymorphic to anaplastic morphology are described. An unfavorable variant are pediatric chordomas with a loss of INI-1. BNCT and chordomas are characterized by the following immunohistological profile: vimentin+, cytokeratin+/-, epithelial membrane antigen (EMA)+/-, S100 protein+/-, brachyury+. This profile helps to distinguish these tumors from other lesions such as chondrosarcoma, chordoid meningioma, and metastases of carcinoma.

[H3F3A mutated multicentric giant cell tumor of bone : A very rare primary bone disease]. / H3F3A-mutierter multifokaler Riesenzelltumor des Knochens : Eine äußerst seltene primär ossäre Erkrankung.

This article presents the case of a metachronic multicentric giant cell tumor of bone (GCTB). The patient obtained his first diagnosis of GCTB in the left humerus at the age of 47 years. Furthermore, he suffered from a GCTB in the head of his 4th left metacarpal bone and from a recurrence of the latter. All tumors carried the characteristic H3F3A mutation, which was proven by Sanger sequencing and a mutation specific antibody. The case is the first description of a multicentric H3F3A mutated GCTB.

[Cystic echinococcosis and hepatocellular carcinoma--a coincidence? A case report]. / Zystische Echinokokkose und hepatozelluläres Karzinom--zufällige Koinzidenz? Ein Fallbericht.

INTRODUCTION: The coincidence of echinococcosis and hepatocellular carcinoma (HCC) is quite rare. We report the case of a 45-year-old man who was admitted to our hospital because of abdominal pain in the right upper quadrant and jaundice. Clinical features and diagnostics: There was no history of weight loss or fever. No abdominal mass was palpable. The laboratory reports showed increased transaminase levels. Ultrasonography revealed an inhomogenous, cystic lesion measuring 6 cm in diameter in the segments VI and VII. Serology for echinococcosis was negative, alpha-fetoprotein (AFP) was considerably increased. CT scan showed a solid mass of 3,7 cm in diameter adjacent to the cystic lesion. THERAPY AND COURSE: Anthelminthic therapy with albendazole caused a massive increase of cholestasis parameters and treatment had to be stopped. The simultaneous occurrence of serologically negative cystic echinococcosis and HCC was suspected and partial liver resection was performed. Histological examination confirmed both diagnoses and tumor resection in healthy tissue. 5 months after resection CT scan showed multicentric HCC affecting the whole liver. Palliative therapy with sorafenib was established. DISCUSSION: The coincidence of HCC and cystic echinococcosis in the non-cirrhotic liver of a young man is a rare event. Despite resection in healthy tissue multicentric HCC was diagnosed 5 months later. Only few cases of simultaneous occurrence of HCC and echinococcosis have been published so far. Some authors considered echinococcosis as a trigger for HCC. A causal link between both entities has not been demonstrated until now.

[Gastric lymphoma: still an interdisciplinary challenge]. / Das Lymphom im Magen: Eine persistierende interdisziplinäre Herausforderung.

Differentiation of chronic gastritis from marginal zone B-cell lymphoma (MZoL) of MALT type is often difficult for the pathologist. Diagnostic tools include CD20 stain to highlight lymphoepithelial lesions, Wotherspoon grading of the infiltrate, and clonality analysis of the B-cells. MZoL may partially transform into a diffuse, large B-cell lymphoma, which the authors have named blastic MZoL. Blastic MZoL may be present with or without small cell MZoL. Without this component, blastic MzoL, while being CD10-negative, is presently difficult to positively diagnose since specific immune markers are still lacking. Blastic MZoL has a very favourable outcome compared to conventional diffuse large B-cell lymphomas (DLBCL). Moreover, there are conventional DLBCL in the stomach, mostly in a setting of a secondary organ involvement. The biology of these gastric DLBCL is identical to their extragastric counterparts. This is also true for primary gastric Burkitt lymphoma and mucosal involvement in B-CLL or mantle cell lymphoma. Unfavourable outcomes are always observed for EBV-triggered lymphoproliferations in immunodeficiency and peripheral T-cell lymphomas which might also arise or be initially diagnosed in the stomach.

[Round robin test for detection of genomic aberrations in non-Hodgkin lymphoma by in situ hybridization]. / Ringversuch zum Nachweis genomischer Veränderungen bei Non-Hodgkin-Lymphomen mittels In-situ-Hybridisierung.

BACKGROUND: The detection of characteristic genomic aberrations by fluorescence in situ hybridization (FISH) has a high diagnostic impact on lymphomas according to the World Health Organization (WHO). To investigate the reproducibility of non-isotopic ISH results a multicenter trial was carried out involving eight institutes for hematopathology. MATERIAL AND METHODS: Analyses were performed on two diffuse large B-cell lymphomas (DLBCL) without known aberrations, on one follicular lymphoma with a IGH/BCL2 translocation and BCL6 split and on two B-cell lymphomas intermediate between DLBCL and Burkitt's lymphoma with c-MYC and BCL2 rearrangements, one with an additional BCL6 split. Break-apart probes for BCL6 and c-MYC, as well as fusion probes for the c-MYC/IGH and the IGH/BCL2 translocations were used. RESULTS: All aberrations were correctly detected by all centres and no false positive or false negative results were obtained. The numbers of positive cells varied from 25% to 94%. Pearson's correlation coefficient between the centres was always > 0.8. CONCLUSIONS: The ISH analysis of recurrent genomic aberrations in formalin-fixed paraffin-embedded (FFPE) tissue is a highly reproducible technique which yields substantial additive help for lymphoma diagnostics.

[Chordoma-An update]. / Chordome ­ Ein Update.

Chordomas are rare malignant tumors of the axial skeleton with notochordal differentiation. From a morphological point of view, chordomas display a broad spectrum ranging from the classical, conventional form not otherwise specified (NOS) to forms with hepatoid or renal carcinoma-like differentiation or even poorly or dedifferentiated variants. The detection of brachyury is highly characteristic, though not exclusive. The morphological differential diagnosis from a benign notochordal tumor (BNCT) requires integration of imaging since BNCT is limited to the vertebral bodies and is not osteolytic. Targeted therapy is a current research focus and cell lines as in vitro models are a precondition for the establishment and validation of this approach.

Acute Pancreatitis in a patient with hypercalcemia due to tertiary hyperparathyroidism.

Hypercalcemia represents an independent risk factor of acute pancreatitis and can result from hyperfunctioning parathyroid glands. Here, we report on a 35-year-old patient who was admitted to our hospital with abdominal pain six weeks after kidney transplantation. Based on laboratory tests and ultrasound imaging, acute pancreatitis with hypercalcemia due to tertiary hyperparathyroidism was diagnosed. Subsequently, the patient was treated by parathyroidectomy with autologous tissue transplantation. This constellation points to acute pancreatitis as a very rare and severe complication of patients developing tertiary hyperparathyroidism-related hypercalcemia from secondary hyperparathyroidism after kidney transplantation.

Difficult diagnosis of a large cystic retroperitoneal tumor mimicking a hepatic origin.

Schwannomas are rare tumors, usually benign, originating from the nerve sheath, and found only infrequently in the retroperitoneal space. We report on a 67-year-old woman who was initially misdiagnosed and treated for a liver hydatid cyst. After incomplete resection and recurrence of the tumor, we were able to diagnose a large retroperitoneal schwannoma that completely displaced the liver to the left abdomen. The patient underwent surgical resection of the schwannoma; pathological evaluation revealed a cystic tumor measuring 18.5 × 18 × 12.5 cm, with tumor cells staining strongly positive for S-100. Retroperitoneal schwannomas may mimic cystic hepatic tumors and should, therefore, be considered as a differential diagnosis in such cases. We describe the diagnostic modalities and difficulties in the approach of a cystic liver tumor.

Comparison of sonographically measured bowel wall vascularity, histology, and disease activity in Crohn's disease.

The purposes of this study was to provide a retrospective comparison of semiquantitatively measured bowel wall vascularity by power Doppler sonography, endoscopic-histopathological biopsy findings, and disease activity in patients with confirmed Crohn's disease. Thirty-two out of 1,332 patients with histologically confirmed Crohn's disease (18 female, 14 male; mean age 38.8 years) met the inclusion criteria: ileocolonoscopy with biopsy and power Doppler sonographic determination of bowel wall vascularity with assessment of disease activity within a period of 5 days. Sonographic determination of bowel wall vascularity was based on a semiquantitative score. Endoscopic bowel wall biopsy specimens were assessed using a self-developed inflammation score and the disease activity was calculated using Crohn's disease activity index (CDAI). A significant association (p < 0.05) was shown for results of histology and bowel wall vascularity in the terminal ileum (kappa = 0.66; sensitivity 95%; specificity 69%). There was no observed association between CDAI and histology, although there was an association between CDAI and bowel wall vascularity (sensitivity 82%). Increased bowel wall vascularity in the terminal ileum measured by power Doppler ultrasound reflects inflammatory activity in histologically examined bowel wall. Power Doppler ultrasound may be able to monitor activity changes of the bowel wall determined by pharmaceutical treatment.

Anorectal amelanotic melanoma.

OBJECTIVE: Anorectal melanoma is a rare, highly malignant tumour with a poor 5 year survival of 10%. Most anorectal melanomas have gross and/or histologic pigmentation, however about 30% of anorectal melanomas are amelanotic. METHOD: We report three cases of amelanotic anorectal melanomas and integrate our data with six case reports of amelanotic malignant melanoma from the literature. Further we compare clinicopathological data and clinical outcome with large series of anorectal melanomas (both, amelanotic and pigmentated). RESULTS: There were seven females and two males, of median age 62 years (range: 45-75 years). Rectal bleeding was the leading symptom in all cases with a mean duration of 4 months before diagnosis. Eight of nine patients developed distant metastases. Median survival was 14 months (range: 3-60 months). A tumour thickness of < 4 mm was correlated with long-term disease-free survival, whereas tumour thickness of 4 mm or more was correlated with systemic recurrence. CONCLUSION: Early diagnosis is key for efficient treatment and improved survival rate for patients with this unusual variant of melanoma. There is no difference in terms of age, time of diagnosis, stage and survival between pigmented and amelanotic anorectal melanoma.

[U-HO1. A new cell line derived from a primary refractory classical Hodgkin lymphoma]. / U-HO1. Eine neue Zelllinie, abstammend von einem primär therapierefraktären klassischen Hodgkin-Lymphom.

The Hodgkin cell line U-HO1 was established from a malignant pleural effusion of a 23-yr-old male patient during the end stage of refractory nodular sclerosing classical Hodgkin lymphoma (cHL). Since its establishment in 2005, U-HO1 has maintained stable characteristics in vitro and has a doubling time of about 4 days under standard culture conditions. U-HO1 forms typical Reed/Sternberg cells in suspension, is EBV negative, lacks HLA-ABC- but expresses HLA-D- proteins/CD74 and surface exposes CD15 together with CD30 in the absence of CD19 and CD20. Karyotype analysis of U-HO1 revealed a hyperdiploid karyotype with multiple clonal aberrations. Most significant is an elongated chromosome 2, der(2)t(2;10)(q35;q16.1)add(2)(p13). CGH analysis revealed the following imbalances: ish cgh dim(1)(p13p31)(p12q21), enh(2)(p13p23), dim(4)(q31.3qter), enh(6)(q22q27), enh(12), enh(18),enh(20)(q13.1pter). FISH analysis showed about six-fold amplification of REL and BCL-11A, thus, U-HO1 is prototypical for cHL in every aspect tested so far. Compared to other HL cell lines, U-HO1 proved far less genetically aberrant suggesting that U-HO1's imbalances suffice to cause the full-blown phenotype of primary refractory cHL.

Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation.

The suppressors of cytokine signaling (SOCS) are critically involved in the regulation of cellular proliferation, survival, and apoptosis via cytokine-induced JAK/STAT signaling. SOCS-1 silencing by aberrant DNA methylation contributes to oncogenesis in various B-cell neoplasias and carcinomas. Recently, we showed an alternative loss of SOCS-1 function due to deleterious SOCS-1 mutations in a major subset of primary mediastinal B-cell lymphoma (PMBL) and in the PMBL line MedB-1, and a biallelic SOCS-1 deletion in PMBL line Karpas1106P. For both cell lines our previous data demonstrated retarded JAK2 degradation and sustained phospho-JAK2 action leading to enhanced DNA binding of phospho-STAT5. Here, we analysed SOCS-1 in laser-microdissected Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL). We detected SOCS-1 mutations in HRS cells of eight of 19 cHL samples and in three of five Hodgkin lymphoma (HL)-derived cell lines by sequencing analysis. Moreover, we found a significant association between mutated SOCS-1 of isolated HRS cells and nuclear phospho-STAT5 accumulation in HRS cells of cHL tumor tissue (P < 0.01). Collectively, these findings support the concept that PMBL and cHL share many overlapping features, and that defective tumor suppressor gene SOCS-1 triggers an oncogenic pathway operative in both lymphomas.

[Pathophysiology of bone metastases in urologic carcinomas]. / Pathophysiologie der Skelettmetastasierung urologischer Karzinome.

The skeletal system is the most frequent metastatic site of hematogenous spread of urologic carcinomas. Osseus metastases are classified as osteoneutral, osteolytic, osteoblastic and combinations thereof. Osteolytic metastases lead to bone resorption by activating osteoclasts, while osteoblastic metastases stimulate osteoblasts by paracrine mechanisms. The local osteoblastic effect is associated with secondary systemic bone resorption. The use of bisphosphonates is now an established supportive therapy and newer treatment strategies including targeted intervention in the pathophysiology of bone metastases and radioimmunotherapy are being applied or will be coming soon.

Segmental chromosomal aberrations and centrosome amplifications: pathogenetic mechanisms in Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma?

Tumor cell metaphases of classical Hodgkin's lymphoma (cHL) characteristically display highly rearranged karyotypes with chromosome numbers in the hyperploid range and marked intraclonal variability. The causes of this cytogenetic pattern remain largely unknown. An unusual type of chromosomal abnormality coined as segmental chromosomal aberration (SCA) has been recurrently observed in HL cell lines and was suggested to be associated with ribosomal DNA (rDNA) rearrangements. Moreover, centrosome abnormalities provoking deficient chromosome segregation have been reported in many solid tumors and also in cHL cell lines. Whether SCA, rDNA rearrangements or centrosome abnormalities also occur in primary cHL is not yet known. Thus, we performed extensive molecular cytogenetic and immunohistological studies in two cHL cases. Both cases presented SCA associated with genomic gains of the REL and JAK2 loci, respectively. The SCA involving JAK2 was associated with rDNA rearrangements. The absolute centrosome size of HRS cells in both cases was significantly larger than in non-HRS cells, but the relative centrosome size of HRS cells corrected for nuclear size was in the same range as that of the non-neoplastic cells. These findings demonstrate that the various mechanisms associated with chromosomal instability warrant a more detailed characterization in cHL.

Different biological risk factors in young poor-prognosis and elderly patients with diffuse large B-cell lymphoma.

Prognostically relevant risk factors in patients with diffuse large B-cell lymphoma (DLBCL) have predominantly been evaluated in elderly populations. We tested whether previously described risk factors are also valid in younger, poor-prognosis DLBCL patients. Paraffin-embedded samples from 112 patients with de novo DLBCL, enrolled in the R-MegaCHOEP trial of the German High Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) were investigated using immunohistochemistry (MYC, FOXP1, LMO2, GCET1, CD5, CD10, BCL2, BCL6, IRF4/MUM1) and fluorescence in situ hybridization (MYC, BCL2, BCL6). MYC, BCL2 and BCL6 breaks occurred in 14, 21 and 31%, respectively. In the majority of cases, MYC was simultaneously rearranged with BCL2 and/or BCL6. The adverse impact of MYC rearrangements was confirmed, but the sole presence of BCL2 breaks emerged as a novel prognostic marker associated with inferior overall survival (OS) (P=0.002). Combined overexpression of MYC and BCL2 showed only limited association with inferior OS. All immunohistochemical cell of origin classifiers applied failed to predict survival time. DLBCL tumors with significant proportion of immunoblastic and/or immunoblastic-plasmacytoid cells had inferior OS, independently from from BCL2 break. Younger, poor-prognosis DLBCL patients, therefore, display different biological risk factors compared with an elderly population, with BCL2 translocations emerging as a powerful negative prognostic marker.